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Natural Products As Building Blocks and Lead Compounds for API Production

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Natural Products As Building Blocks and Lead Compounds for API Production Doctorate School in Chemical Science - XXIX Cycle Natural products as building blocks and lead compounds for API production PhD Thesis of Cristina MARUCCI R10607 Tutor: Prof. Daniele Passarella Cotutor: Dott. Marcello Luzzani Academic Year: 2015/2016 Ai miei genitori Summary 1. Natural products in drug discovery ................................................................... 10 1.1. Role of nature in drug discovery ................................................................... 11 2. Natural products as building blocks for production of API ............................ 17 2.1. Industrial synthesis of vincamine .................................................................. 18 2.1.1. Introduction ........................................................................................... 18 2.1.2. Biosynthesis ........................................................................................... 21 2.1.3. Total synthesis of vincamine ................................................................. 23 2.1.4. Synthesis of vincamine with tabersonine as starting material ............... 28 2.1.5. Impurities derived from the synthesis of vincamine .............................. 35 2.2. Design of experiment (DOE) ......................................................................... 37 2.2.1. Full factorial design ............................................................................... 40 2.2.2. Reactivity of 3-oxo-tabersonine and 3-oxo-vincadifformine ................ 46 2.3. Lignans .......................................................................................................... 50 2.3.1. Introduction ........................................................................................... 50 2.4. Lignans derivatives ........................................................................................ 55 2.4.1. Synthesis of oxomatairesinol ................................................................. 55 2.4.2. Synthesis of (-)-7(R)-HMR .................................................................... 58 2.5. Experimental part .......................................................................................... 65 2.5.1. General information ............................................................................... 65 3. Isolation and structural characterization of natural products ........................ 77 3.1. Indole alkaloids from Vocanga africana ....................................................... 78 3.1.1. Voacanga africana ................................................................................ 78 3.1.2. Isolation and structure elucidation of Voacanga alkaloids .................... 80 3.2. (-)-Cytisine: natural sources .......................................................................... 87 3.2.1. Introduction ........................................................................................... 87 3.2.2. Biosynthesis ........................................................................................... 91 3.2.3. Total synthesis of the lupin alkaloid cytisine ........................................ 93 3.2.4. (-)-Cytisine derivatives: synthesis of N-formyl and N-methyl derivatives 96 3.3. Experimental part ........................................................................................ 101 3.3.1. General information ............................................................................. 101 4. Natural products as lead compounds ............................................................... 112 4.1. Synthesis of an analogue of the natural product doliculide ......................... 113 4.1.1. Introduction ......................................................................................... 113 4.1.2. Aim of the project and retrosynthetic plan .......................................... 115 4.2. Result and discussion................................................................................... 117 4.2.1. Synthesis of dipeptide .......................................................................... 117 4.2.2. Synthesis of secondary alcohol fragment ............................................ 119 4.2.3. Fragment coupling and completation of the synthesis......................... 122 4.3. Pironetin-dumetorine hybrid compounds .................................................... 124 4.3.1. Introduction ......................................................................................... 124 4.3.2. Docking studies of pironetin ................................................................ 128 4.3.3. Aim of the project and retrosynthetic plan .......................................... 129 4.3.4. Hybrid compounds docking ................................................................. 131 4.4. Result and discussion................................................................................... 132 4.4.1. Synthesis of hybrid compounds ........................................................... 132 4.4.2. Biological evaluation ........................................................................... 136 4.5. Bivalent compounds toward -tubulin interaction ................................... 137 4.5.1. Introduction ......................................................................................... 137 4.5.2. Aim of the work ................................................................................... 139 4.5.3. Synthetic strategy ................................................................................ 141 4.5.4. Biological evaluation and future work ................................................ 143 4.6. Experimental part ........................................................................................ 144 4.6.1. General information ............................................................................. 144 4.6.2. Doliculide fragments synthesis ............................................................ 145 4.6.3. Pironetin-dumetorine hybrid compounds ............................................ 155 4.6.4. Bivalent compounds ............................................................................ 173 4.7. Biological assay ........................................................................................... 176 4.8. Docking Studies ........................................................................................... 177 5. Natural products and cancer stem cells ........................................................... 178 6. Conclusions ........................................................................................................ 198 7. Acknowledgments .............................................................................................. 199 Abstract This dissertetion describes the relevance of natural products as building blocks for production of active pharmaceutical ingredients (API) and as lead compounds. Chapter 1 offers an introduction on the use of natural products as an effective therapeutic and its role on inspiring the discovery of new drugs. Chapter 2 focuses on the importance of natural products as lead compounds for active pharmaceutical ingredients (API) production. In the first part of this chapter the synthesis of vincamine, the major indole alkaloid presents in Vinca minor L., will be discussed. In particular the design of experiment (DOE) applied to the synthesis of vincamine starting from vincadifformine will be described. In the second part of this chapter the semi- synthesis of two lignan derivatives, oxomatairesinol and (-)-7-(R)-hydroxymatairesinol, will be reported. Chapter 3 will focus on the isolation and structural characterization of natural products. The first part describes the isolation and structural characterization of ten indole alkaloids from Voacanga africana (Apocynaceae) seeds. Then the semisynthesis of two cytisine derivatives, N-formyl and N-methyl cytisine, will be described. Chapter 4 describes the role of natural products as lead compounds. The first section illustrate a project that was performed in the laboratory of Prof. Karl-Heinz Altmann (ETH-Zurich, Switzerland) in the frame of COST Action CM1407 (Challenging Organic Synthesis Inspired By Nature: From Natural Product Chemistry To Drug Discovery). It is related to the synthesis of an analogue of the natural product doliculide, a 16- membered depsipeptide, that has been isolated in 1994 from the Japanese sea hare Dolabella auricularia. The second section will focus on the design and synthesis of hybrid compounds. Particularly it will describe the synthesis of pironetin-dumetorine hybrid compounds whose structures are representative of an optimizable lead scaffold for the discovery of new tubulin binders. Another topic here discussed will be the production of bivalent compounds linking two different units, a pironetin-dumetorine hybrid compound and a drug able to bind -tubulin, in order to have a duble action with the aim to limit the the protein-protein interaction between and -tubulin. 8 Chapter 5 offers an overview on the role of natural products in drug discovery, in particular related to cancer stem cells (CSCs). In a recent review we summarized the natural products that demonstrate activity against CSCs. Forty-nine different natural products grouped into several structural classes (such as flavonoids, polyketides, terpenes, alkaloids and many others) will be described. Their structure diversity could suggest the synthesis of libraries of new compounds for a huge exploration of the chemical space of CSCs inhibitors. 9 1. Natural products
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